Chinese clinical studies for pharmacological treatments of coronavirus disease 2019 ( COVID-19 )

Objectives: This study aims to identify, report, and analyze registered and published clinical trials and observational studies for the pharmacological treatment of COVID-19 conducted in China. Methods: A strategic search was conducted via the Chinese Clinical Trial Registry to identify and extract clinical trials and observational studies registered and conducted in China for the pharmacological treatment of COVID-2019 between January 1st, 2020 and March 21st, 2020. This was further supplemented by searches conducted via the China National Knowledge Infrastructure (CNKI) database, the MEDLINE database, the World Health Organization (WHO) database, and MedRxiv and BioRxiv electronic platforms for preprint articles, published up until April 8th, 2020. Studies available in Chinese and English were included in the searches and extracted. A primary descriptive analysis was performed for registered clinical trials and observational studies identified in the Chinese Clinical Trial Registry based on the extraction of the following clinical study information: trial ID, planned date of enrollment, recruitment status, study design, population, sample size, intervention/exposure group, control /reference group, dosage, and primary outcomes. A secondary descriptive analysis was performed for published clinical trials and observational studies identified from the supplementary databases based on the extraction of the following published clinical study information: study design, population, intervention/exposure group, control /reference group and main results as appropriate. Results: A total of 221 clinical trials and observational studies were included from all databases searched. From the Chinese Clinical Trial Registry, 195 registered clinical studies including 170 clinical trials and 25 observational studies were identified and included for primary analysis. From the supplementary databases, 26 published clinical studies including 8 clinical trials and 18 observational studies were included for secondary analysis. Of these 26 published clinical studies, 18 studies, including 3 clinical trials and 15 observational studies were identified from CNKI, 2 studies including 1 clinical trial and 1 observational study from MEDLINE, 2 including 1 clinical trials and 1 observational studies from the WHO database, and 4 including 3 clinical trials and 1 observational studies from MedRxiv and BioRxiv platforms. In the primary analysis, among the 170 clinical trials included from the Chinese Clinical Trial Registry, 101 investigated western medicines (WMs), while 15 investigated Traditional Chinese Medicines (TCMs), and 54 investigated a combination of TCMs and WMs. Among the 25 included observational studies from the Chinese Clinical Trial Registry, 2 investigated WMs, 2 investigated TCMs, and 21 investigated a combination of TCMs and WMs. The total number of exposed patients in all 195 clinical studies from the Chinese Clinical Trial Registry amounted to 24,500. In the secondary analysis, treatment with Lopinavir-ritonavir and treatment with Hydroxychloroquine was not associated with a difference from standard of care in the rate of RT-PCR negativity; treatment with a combination of Lopinavir-ritonavir, interferon α, and Lian-Hua-Qing-Wen capsule was found to significantly improve the effective rate of treatment compared with Interferon α combined with Lian-Hua-Qing-Wen capsule. Conclusions: China is generating a massive source of evidence that is critical for defeating the COVID-19 pandemic. Not only the clinical experience, but also the scientific evidence should be shared with the global scientific community.


Introduction
By the end of December 2019 China announced the identification of a new emerging viral condition [1], caused by a novel coronavirus. The virus was provisionally named 2019-coronavirus (2019-nCoV) [2]and then finally named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The A primary descriptive analysis was performed for registered clinical trials and observational studies identified from Chinese Clinical Trial Registry based on the extraction of the following clinical study information: trial ID, planned date of enrollment, recruitment status, study design, population, sample size, intervention/exposure group, control /reference group, dosage, and primary outcomes. Pharmacological interventions and/or exposures were classified as Western Medicines (WMs), Traditional Chinese Medicines (TCMs), and a combination therapy of WMs and TCMs. WMs were further stratified into antiviral agents, antiparasitic agents, anti-inflammatory agents, biologics, cellbased therapies, plasma therapies, other therapies, and combination therapies of WMs with different mechanisms of action.
The strategic searches of the supplementary databases, CNKI, MEDLINE, WHO, and MedRxiv and BioRxiv platforms, were conducted by employing the following keywords: 1) for the CNKI database: "novel coronavirus", "2019-nCoV", "COVID-19" and "SARS-CoV-2"; 2) MEDLINE: "novel coronavirus" AND "clinical studies", "trials", "observational studies"; 3) WHO database and preprint platforms with all included paper in pharmacology-related subject area. Results from the supplementary database searches were included if: 1) they met the three inclusion criteria also applied to the Chinese Clinical Trial Registry and 2) if they reported study results. A secondary descriptive analysis was performed for published clinical trials and observational studies identified from supplementary databases based on the following extracted clinical study publication information: study design, population, intervention/exposure group, control /reference group and main results as appropriate. The rationale for the use of WMs reported in the included clinical studies for COVID-19 was reported based on published reviews [9] and electronic reports [10,11].
No quality assessment was performed. Two researchers independently conducted the searches and extracted information. Any discrepancies identified between the two researchers were reconciled by a third, independent researcher.

Results
A total of 221 clinical trials and observational studies for pharmacological treatments of COVID-19 were included from all databases searched. From the Chinese Clinical Trial Registry, 195 registered clinical studies, including 170 clinical trials and 25 observational studies, were identified and included for primary analysis. From the supplementary databases, 26 published clinical studies, including 8 clinical trials and 18 observational studies, were included for secondary analysis. Of these 26 published clinical studies, 18 published clinical studies were identified and included from the CNKI, including 3 clinical trials and 15 observational studies, 2 from MEDLINE, including 1 clinical trial and 1 observational study, from MEDLINE, 2 from WHO, including 1 clinical trial and 1 observational study, and 4 clinical studies, including 3 clinical trials and 1 observational study from MedRxiv and BioRxiv electronic platforms. A total of 43 WMs and 42 TCMs were identified in this study and the rationale for WMs in the treatment of COVID-2019 was summarized in Table 1.

Primary analysis for registered clinical studies from the Chinese Clinical Trial Registry Results
Of the 482 COVID-19 related studies registered in the Chinese Clinical Trial Registry as of March 21 st , 2020, a total of 195 clinical studies, comprising of clinical trials (n=170) and observational studies (n=25), were included from the search. The remaining 287 studies were excluded as 1) they were not clinical trials or observational studies (n=53); 2) they did not investigate the effect of pharmacological treatment (n=189); or 3) they were cancelled by the investigators in the trial registry (n=45). Of the 170 included clinical trials investigating the pharmacological treatment effects of WMs (n=101), TCMs (n=15), and a combination therapy of WMs and TCMs (n=54), the sample size ranged from 10 to 1,000 patients. Of the 25 included observational studies investigating the pharmacological treatment effects of WMs (n=2), TCMs (n=2), and a combination therapy of WMs and TCMs (n=21), the sample size ranged from 20 to 2,000 patients. The total number of exposed patients of all the 195 clinical studies included was 24,500.
Fifteen of the clinical trials reported 1 primary outcome, while 5 clinical trials reported more than 1 primary outcome. Time to reverse transcription polymerase chain reaction (RT-PCR) negativity (n=7), rate RT-PCR negativity (n=7), rate of composite adverse outcomes (n=4), and time to clinical recovery (n=3) were the most reported primary outcomes (  Table 2).
Eleven of the clinical trials reported 1 primary outcome, while 9 clinical trials reported more than 1 primary outcome. Time to RT-PCR negativity (n=3) and time to clinical recovery (n=3) were the most reported primary outcomes ( Table 3) Clinical trials of antiparasitic agents Of the 16 included trials for antiparasitic agents (Table 4), 11 trials were currently recruiting as planned and most trials (n=11) were RCTs with sample sizes ranging from 10 to 320 patients. Three antiparasitic agents were investigated, including Chloroquine Phosphate (n=10), Hydroxychloroquine (n=8), and Suramin sodium (n=1).
Eleven of the clinical trials reported 1 primary outcome, while 5 clinical trials reported more than 1 primary outcome. Time to RT-PCR negativity (n=7) and time to clinical recovery (n=5) were the most reported primary outcomes (Table 4).

Clinical trials of cell-based therapies
Of the 11 included trials for cell-based therapies (Table 5), 3 trials were currently recruiting as planned. Most trials (n=8) were RCTs with sample sizes ranging from 16 to 63 patients. Two different cell-based therapies, Mesenchymal stem cells and its exosomes (n=10) and Human natural killer cellsmesenchymal stem cells (n=1), were investigated.
One clinical trial did not report any primary outcomes, 6 clinical trials reported 1 primary outcome, and 4 clinical trials reported more than 1 primary outcome. Chest CT (n=4) and clinical symptoms (n=2) were the most reported primary outcomes (Table 5).
Clinical trials of plasma therapy Of the 11 included trials for plasma therapies (Table 6), 9 trials were currently recruiting as planned and most trials (n=7) were RCTs with the sample sizes ranging from 10 to 200 patients. Four different plasma therapies were investigated, including Convalescent plasma (n=7), Anti-2019-nCoV virus inactivated plasma (n=3), immunoglobulin of cured patients (n=1), and Umbilical plasma (n=1).
Eight of the clinical trials reported 1 primary outcome, while 3 clinical trials reported more than 1 primary outcome. Clinical symptoms (n=3) and time to clinical improvement (n=2) were the most reported primary outcomes (Table 6).
Four of the clinical trials reported 1 primary outcome, while 2 clinical trials reported more than 1 primary outcome. Time RT-PCR negativity (n=2) was the most reported primary outcome (Table 7).
All of the clinical trials (n=6) reported 1 primary outcome. The rate of RT-PCR negativity (n=3) was the most reported primary outcome (Table 8).

Clinical trials of WM combination therapies
Of the 11 included trials for WM combination therapies (Table 9), 10 trials were currently recruiting as planned and most trials (n=9) were RCTs with sample sizes ranging from 30 to 150 patients. Nine trials investigated the effects of antivirus agents combined with biologics (n=7), an antiparasitic agent (n=1) or a biologic plus anti-inflammatory agent (n=1), while 2 trials investigated 2 cell-based therapies combined with a biologic (n=1) or an anti-inflammatory agent (n=1).
Eight of the clinical trials reported 1 primary outcome, while 3 clinical trials reported more than 1 primary outcome. Chest CT (n=4) was the most reported primary outcome (Table 9).

Clinical trials of TCMs
Of the 15 included trials for TCMs, 9 trials reported the specific names of investigated TCMs. Of these 9 trials, specifying TCMs (Table 10), 4 trials were currently recruiting as planned and most trials (n=6) were RCTs with sample sizes ranging from 60 to 400 patients. Thirteen different TCM compounds were investigated in these 9 trials specifying TCMs.
Five of the clinical trials reported 1 primary outcome, while 4 clinical trials reported more than 1 primary outcome. Clinical symptoms (n=3) was the most reported primary outcome (Table 10).

Clinical trials of WM and TCM combination therapies
Of the 54 included trials for WM and TCM combination therapies, 31 trials reported the specific names of investigated TCMs. Of the 31 trials specifying TCMs combined with WMs (  Table 11), 21 trials were currently recruiting as planned and most trials (n=26) were RCTs with sample sizes ranging from 20 to 408 patients. Thirty-six different TCM compounds were combined with standard of care (SOC) (n=33), lopinavir-ritonavir(n=10), lopinavir-ritonavir + Interferon α2b (n=1), and Umifenovir (n=1) in these 31 trials specifying TCMs.
Twenty-one of the clinical trials reported 1 primary outcome, while 10 clinical trials reported more than 1 primary outcome. Chest CT (n=8), time to clinical recovery (n=7), and clinical symptoms (n=7) were the most reported primary outcomes (Table 11).

Observational studies of pharmacological treatments for COVID-19 in China
Of the 25 included observational studies for pharmacological treatments, 6 studies reported the specific names of investigated interventions, while the others (n=19) did not. Two WMs, including antivirus agents plus biologics (n=1) and a cell-based therapy (n=1) were investigated, while 3 TCMs, including Qing-Fei detoxification (n=2), Triple energizer (n=1), and Xin-Guan-1 formula (n=1) were investigated. Of the 6 observational studies specifying interventions (  Table 12), 4 studies were currently recruiting as planned and 1 study was completed. Half of the studies (n=3) were cohort studies with sample sizes ranging from 100 to 237 patients and the other half of studies (n=3) were case series with sample sizes ranging from 20 to 100 patients.
Two of the observational studies reported 1 primary outcome, while 4 observational studies reported more than 1 primary outcome. Chest CT (n=2) and blood routine tests (n=2) were the most reported primary outcomes (  Table 12). analysis for published clinical studies from supplementary databases: CNKI, MEDLINE,  WHO, and MedRxiv and BioRxiv Platforms  From the supplementary searches of the CNKI, MEDLINE, WHO, and MedRxiv and BioRxiv platforms,  a total of 27 published clinical studies, including 8 clinical trials and 19 observational studies

Published clinical trials from supplementary searches
Of the 8 included trials (Table 13), all trials were RCTs with sample size ranging from 30 to 240 patients; and 7 different interventions were investigated, including 5 WMs and 2 TCMs combined with WMs. Treatment with Lopinavir-ritonavir (n=99) was not associated with a difference from SOC (n=100) in the time to clinical improvement (p>0.05) and mortality at 28 days (19.2% vs. 25.0%, p>0.05). Treatment with Lopinavir-ritonavir (n=21) or Umifenovir (n=16) was not associated with a difference from SOC with no antiviral drugs (n=7) in time of positive-to-negative conversion of SARS-CoV-2 nucleic acid, the rates of antipyresis, cough alleviation, improvement of chest CT or the deterioration rate of clinical status (all P > 0.05). Treatment with Ribavirin + Lopinavir-ritonavir + Interferon α (n=21) was not associated with a difference from Lopinavir-ritonavir + Interferon α (n=46) in time to RT-PCR negativity and days of hospitalization; treatment with Favipiravir + SOC (n=116) was associated with a difference from Umifenovir + SOC (n=120) in clinical recovery rate of day 7 (71.43% vs 55.86%, P=0.0199), fever reduction and cough relief (P<0.001); More adverse events (13.79% vs 2.50%, P<0.0001); treatment with Hydroxychloroquine (n=15) was not associated with a difference from SOC (n=15) in rate of RT-PCR negativity (86.9% vs. 93.3%. p>0.05); treatment with Hydroxychloroquine + SOC (n=31) was associated with a difference from SOC (n=31 ) in time to clinical recovery and proportion of patients with improved pneumonia (80.6% vs 54.8%); treatment with Lopinavir-ritonavir+ interferon α + Lian-Hua-Qing-Wen capsule (n=30) was found to significantly improve effective rate of treatment (76.7% vs. 46.7%, p<0.01) compared with Interferon α + Lian-Hua-Qing-Wen capsule (n=30) ; and treatment with Tou-Jie-Qu-Wen Granule + Umifenovir (n=20) was found to significantly improve the TCM syndrome score, absolute value of lymphocyte and value of C reactive protein compared with Umifenovir alone (n=17) ( Table 13).

Published observational studies from supplementary searches
Of the 18 included observational studies (Table 14), most studies (n=14) reported the specific name of all investigated interventions in the publications, while the others (n=4) did not report the name of investigated TCMs. Most of the studies (n=12) were retrospective case series with sample sizes ranging from 10 to 463 patients, while the remaining studies (n=6) were retrospective cohort studies with sample sizes ranging from 28 to 134 patients. Twelve different interventions were investigated including 10 WMs and 3 TCMs. Treatment with Lopinavir-ritonavir + Interferon α + Symptom treatment (n=52) and Umifenovir + Interferon α + Symptom treatment (n=34) were not associated with a difference from Interferon α + Symptom treatment (n=48) in rate of RT-PCR negativity (71.8% vs. 82.6% vs. 77.1%, P= 0.79) and a difference in number of patients still in progress (22 vs 13 vs 25, P=0.3). Treatment with Umifenovir + Lopinavir-ritonavir (n=16) was associated with a difference from Lopinavir-ritonavir (n=17) in the rate of RT-PCR negativity (75% vs 35%, P<0.05) and chest CT (69% vs 29%, P<0.05); treatment with Meplazumab + SOC (n=17) was associated with a difference from SOC (n=11) in the discharged (p=0.006) and case severity (p=0.021) in critical and severe patients; and treatment with Shu-Feng-Jie-Du Capsule (n=35) was found to significantly improve the symptoms and time to RT-PCR negativity (p<0.05) compared with Umifenovir alone (n=35) (Table 14).

Discussion
A total of 195 clinical studies, comprising of clinical trials (n=170) and observational studies (n=25), were included from the Chinese Clinical Trial Registry. Altogether, 24,500 patients were planned to be exposed in these clinical studies. Among the 170 clinical trials involving 17,151 patients, 101 tested WMs, 15 tested TCMs, and 54 tested a combination of TCMs and WMs. 129 of these were RCTs. Currently, 113 clinical trials were still recruiting, however, it is expected that most studies have finished their enrollment because they have at least run for more than one month and may not take more than three weeks to finalize the enrollment during the period of COVID-19 pandemic outbreak.
The numbers of registered clinical studies and exposed patients in China are very impressive and suggest a massive knowledge has been acquired from China as what is presented in this paper is only clinical experience and does not include the critical experience of radiologists and virology laboratories.
TCMs remain of high interest within the Chinese medical community and despite WMs being studied as well, there is still a significant place for TCMs. However, there were still more WMs and combination therapies of WMs and TCMs being studied than TCMs.
The rationale for testing a specific product or a combination of products is not always provided in clinical trials and observational studies. However, several rationales for the investigation of WMs may be considered in the case of this outbreak, such as interventions that have been shown to be effective with other coronaviruses, SARS-COV-2 in vitro, and other viruses as well as interventions that may control the cytokine release, that are based on Mesenchymal stem cells therapies, and interventions with antibodies from patients already recovered from the disease. In relation to TCMs, one of the main concepts of TCM theory is the balance of Yin and Yang, which have been utilized as interventions against COVID-19 to enhance immune defense, relieve fever, restore biological and physiological imbalance, inhibit virus and bacteria, and reduce the inflammatory response of the body caused by the virus and bacteria in mild and moderate patients as well as to gain time and ultimately rescued patients in sever conditions [38]. TCMs were considered not only as adjuvant therapies but also as curative therapies in the COVID-19 outbreak in China and recommended by Chinese clinical guidelines for COVID-19 issued by the National Health Commission of the People's Republic of China [39].
The gold standard of a clinical trial study design is the double-blinded RCT. The process of developing a golden standard clinical trial is unlikely to be feasible within the context of a pandemic outbreak, due to the several months it usually requires to secure pharmaceutical development quality control testing. Therefore, it may be understandable that the studies conducted were not double blinded. As the majority of trials were randomized, this may still guarantee a high likelihood of comparability between treatment arms of the clinical trials. The comparator in gold standard RCTs is always SOC. It is unclear if SOC has been standardized to be comparable in the trials identified and included in this paper. However, in the context of a pandemic outbreak, specifically COVID-19, the SOC would be to ensure vital functions were maintained, especially respiratory functions. Therefore, SOC among the trials identified and included would likely be very similar, especially due to the vast amount of published guidelines in China for the medical management of COVID-19, specifically in relation to the maintenance of respiratory functions.
It will be important to ensure that concomitant therapies, such as biotherapies, corticosteroids, and non-steroid anti-inflammatory drugs, among others, are proportionally used in comparative arms to a reasonable degree. However, it is important that biological, viral analysis, and thoracic imaging are blinded.
In the case of a pandemic outbreaks, such as COVID-19, tensions arise in healthcare systems and strain is placed on the availability of human resources, material resources, and pharmaceuticals. Due to pharmaceutical scarcity, it is possible that clinical trial procedures may not have been fully respected, therefore, potentially introducing biases. However, as several trials were performed for each intervention, a meta-analysis could be performed and may provide robust outcomes integrating the variability of these trials and estimating the effect size of these interventions.
The large number of trials currently registered in China and still open to recruitment, has led to the relative paucity of publications of study results. However, the international scientific community has been eager for the scientific communication and exchange of the large knowledge accumulated in China on the treatment of COVID-19.
It is surprising that WHO has not acted to ensure the expedited dissemination of the continuously accumulating knowledge in China. There is no public evidence of any third party advocating to Chinese authorities to publicly share the vast knowledge accumulated in China.
Other challenges while performing clinical trials for this particular condition is that a large number of patients of patients are asymptomatic and may recover without being aware of their infection statues and, ultimately, without treatment. For mild and moderate patients, SOC followed the guidance of the "Diagnosis and Treatment Protocol for COVID-19 Pneumonia" published by the Chinese National Health Commission [39] has proven to be effective.
Therefore, additional pharmacological treatments other than SOC should be targeted towards to highrisk or very high-risk patients who will eventually end up in intensive care. Treating patients too early may result in a significant number of spontaneously resolved cases, which would require large clinical trial sample sizes to derive conclusions. Treating patients too late may result in the treatment of patients for which the virus is likely cleared, or the inflammatory lesions and bacterial infection as consequences of being infected with the virus will be life threatening. Defining the optimal patient populations and time of enrollment for a COVID-19 trial may be as important as the treatment's effectiveness. Analysis of patient subgroups based on different criteria, including virologic load and further investigation of infection severity level of included patients in clinical trial data may be informative to address these issues.
A great deal of attention has been brought to the possible benefits of chloroquine and derivatives, the broadly used antimalarial drugs. Researchers from the Wuhan Institute of Virology [40] evaluated in vitro 5 FDA-approved drugs and 2 broad spectrum antivirals against a clinical isolate of SARS-CoV-2 and concluded that "chloroquine is highly effective in the control of 2019-nCoV infection in vitro" and that its "safety track record suggests that it should be assessed in human patients suffering from the novel coronavirus disease." Researchers from Wuhan University published a report on the use of hydroxychloroquine and found that, among 80 systematic lupus erythematosus patients treated with hydroxychloroquine, none of them were infected with SARS-CoV-2 during the outbreak.
More recently, researchers from the Shanghai University attributed the ability to control the outbreak of COVID-19 in their hospital to the systematic introduction of chloroquine and hydroxychloroquine beginning on February 5 th , 2019. Researchers from the Qingdao University indicated that "according to the news briefing, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course." In France, a clinical study in Marseille [41] reported a 100% viral clearance in nasopharyngeal swabs in 6 patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin. The French Ministry of Health recently allowed the use of hydroxychloroquine to treat COVID-19 disease pending the results of ongoing clinical trials. However, an observational study in Paris [42] reported that repeated nasopharyngeal swabs in 10 patients using a RC-PCR assay were still positive for SARS-CoV2 RNA in 8/10 patients at days 5 to 6 after treatment initiation. Within 5 days, one patient died, two were transferred to the ICU, and one patient discontinued because of cardiotoxicity. In the absence of virologic or clinical benefit of chloroquine in a number of viral infections, the option of using chloroquine in the treatment of SARS-CoV-2 should be examined with attention in light of the recent promising announcements. Two new observational studies from Marseille support the use of hydroxychloroquine in association with Azithromycin [41, 43]. The last one [43] gather data among 1， 061 treated patients they observed 98% cure, 4% of hospitalisation including 1% in ICU and 0.5% death. Current death rate in 3.5% globally and the lowest one in Germany and Korea is 2%.
In Chinese governmental treatment guideline for COVID-19 [44], chloroquine and hydroxychloroquine appeared as the pillar therapy for COVID-19. It remains unfortunate that more knowledge has not been shared about the selection rationale and associated outcome of using hydroxychloroquine at this point on time of the pandemic may severely target Africa. In Africa, the healthcare infrastructure is totally unable to absorb the consequences of a pandemic that will affect up to one-third or more of the population. The experience-based treatment guidelines may not be enough and more evidence must be generated to facilitate the dissemination of not only clinical experience, but also the scientific evidence from China and their ability to overcome the outbreak to the rest of the world.
Physical distancing is unlikely feasible in Africa due to cultural standards and extreme poverty. People currently live with immediate and extended families in a single room housing up to 20 people or more. In large cities and large city suburbs, rooms with several large families are built one next to other with no clear separation of property. It is also common cultural practice and courtesy that when someone falls ill, all the relatives and close friends visit with the ill to check on them and spend time. Most people in Africa are living off of informal work and are paid daily as it is non-contractual. These daily wages feed their large families and they will face the decision as to whether they will respect confinement measures put in place, risking the loss of their daily salary, and, ultimately, being unable to feed their families, or they will leave confinement to work and as a byproduct disseminate the coronavirus. To battle COVID-19, they have been recommended to wash their hands repeatedly while a vast majority do not have access to water and if they do, they must carry it by hand across long distances. Moreover, they have little access to soap. They are recommended to blow their nose in disposable handkerchiefs, which may not even be affordable. They are recommended to sneeze in their elbows while they mostly dress short sleeves during the hot summer season.
Obviously without an effective pharmaceutical that is affordable like hydroxychloroquine or chloroquine a disaster is brewing in Africa and other countries, such as India. The lack of WHO clear recommendations for using the ammunition considered by Chinese as one of the ultimate options to control pandemic may have long term consequence on WHO's credibility in developing countries. Instead WHO continues to provide inapplicable guidance and warns against the use of chloroquine. WHO's credibility has been questioned during the Ebola, Zika, and Chikungunya outbreaks [45].

Conclusion
China is generating a massive source of evidence that is critical for defeating the COVID-19 pandemic. The authors encourage Chinese scientists to share this knowledge. The knowledge about TCMs is likely difficult to transfer in a short time for an outbreak. It deserves further analysis. Among all tested pharmacological agents, evidence and guidelines in China points toward hydroxychloroquine and chloroquine being the effective therapies, but this observation is mainly based on the clinical experience and limited published studies. However, evidence has accumulated ex-China to support the benefit of hydroxychloroquine in the treatment of COVID-19. More evidence is under generation and should be shared with the global scientific community.